Heparanase is present in a variety of cells such as platelets, leukocytes, endothelial cells and smooth muscle cells, as an enzyme that specifically degrades heparan sulfate chains in various types of heparan sulfate proteoglycan. In the skin, in particular, it is produced by epidermal keratinocytes composing the epidermis and fibroblasts or vascular endothelial cells of the dermis. Its production is also known to be elevated in various types of cancer cells.
Heparan sulfate proteoglycan (HSPG), which is degraded by heparanase, is a polymer found in various animal tissue cell surfaces and extracellular matrices, and it is known to have functions including extracellular buildup of heparan sulfate-binding growth factors (bFGF (basic fibroblast growth factor), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), HB-EGF (heparin binding EGF-like growth factor), and the like).
Perlecan, a type of heparan sulfate proteoglycan, is also present in the epidermal basal membrane at the interface between the epidermis and dermis, and it binds heparan sulfate-binding growth factors to the epidermal basal membrane, controlling migration of growth factors between the epidermis and dermis. Perlecan also controls growth factors for epidermal basal cells that bind to the basal membrane, and it has been shown to be essential for proper growth and differentiation of the epidermis. Consequently, decomposition of perlecan heparan sulfate chains by activation or accelerated expression of heparanase disturbs release of accumulated growth factors and control of growth factors in the epidermis and dermis, leading to failure of control of differentiation and growth of the epidermis and thickening of the dermis, and promoting formation of wrinkles (see PCT/JP2009/056717). In other words, inhibition of heparanase activity suppresses the release of growth factors that accompanies decomposition of heparan sulfate, and allows migration of growth factors between the epidermis and dermis to be controlled, thereby aiding in anti-aging of the skin.
A link between heparanase and cancer malignancy has also been suggested. In particular, it is known that cancer cells with increased production of heparanase have higher proliferative and metastatic ability, and increased inducibility of angiogenesis (Non-patent document 1). Heparanase is also known to have a function of accelerating wound healing (Non-patent document 2). Therefore, effective inhibition of heparanase activity is effective for purposes including suppressing proliferation or metastasis of cancer cells, and suppressing angiogenesis.